PROJECT ABSTRACT Obesity disproportionately impacts sexual minority women. The goal of this K23 is to improve obesity treatments for sexual minority women by tailoring and optimizing an evidence-based online behavioral weight loss program to enhance weight loss in this group. This objective aligns with the research priorities outlined in NIH?s Notice of Special Interest in Research on the Health of Sexual and Gender Minorities (NOT-MD-19-001). Behavioral weight loss programs are the gold standard treatment for mild to moderate obesity. Rx Weight Loss is an online behavioral weight loss program (co-developed by mentors on this K23) that is effective, low-cost, and highly scalable. However, existing research and the Candidate?s pilot work suggest that tailoring treatment to address 3 well-established weight loss barriers in sexual minority women will be critical for maximizing the relevance and efficacy of behavioral weight loss for this group. This K23 will tailor Rx Weight Loss to address sexual minority women?s weight loss barriers (i.e., minority stress, low social support, negative body image) and conduct an optimization trial to identify whether and how tailored components enhance weight loss outcomes in sexual minority women using the Multiphase Optimization Strategy (MOST). The Preparation Phase (Aim 1) will involve developing 3 novel treatment components targeting sexual minority women?s weight loss barriers and refining the intervention based on pilot testing and feedback from qualitative interviews with 20 sexual minority women. The Optimization Phase (Aim 2) will involve conducting a factorial experiment. 88 sexual minority women will receive 12 weeks of Rx Weight Loss and randomization to receive 0-3 tailored components. This data will be used to determine whether novel components - alone and in combination - impact mean weight loss and the proportion of women achieving clinically significant weight loss at 6 months (Aim 2A) and to clarify how tailored components affect weight loss by testing hypothesized mechanisms of action (Aim 2B). Novel components that increase mean weight loss by ?2% or the proportion achieving 5+% weight loss by ?10% will be retained in a final obesity treatment package to evaluate in a future RCT. This project builds on the Candidate?s prior work in sexual minority women and will be completed with guidance from a highly qualified and experienced mentorship team. The Candidate?s overarching goal in this K23 is to establish skills in applying cultural tailoring and innovative methods (e.g., technology- based treatment, MOST) to improve the relevance, efficacy, and impact of behavioral weight loss programs for sexual minority women. The mentorship, training, and experience provided by the K23 will allow the Candidate to acquire these skills and to launch an independent research career leveraging these skills to address obesity disparities in sexual minority women and other underserved groups.